Sulfur inhibitors of phospholipase A-Z

ABSTRACT

Phospholipase A 2  inhibitors having the formula ##STR1## wherein R&#34; is a C 2  -C 20  alkyl group, R 1  &#34; is a C 1  -C 4  alkyl group, y is an integer from 2 to 10, and J -  is a pharmaceutically acceptable anion, are described.

This application is a continuation-in-part of Ser. No. 07/366,426, filedJun. 15, 1989, now abandoned, which is a divisional application of Ser.No. 07/434,967, filed Nov. 8, 1989, which is now U.S. Pat. No.4,981,989, issued Nov. 1, 1991, which is a divisional application ofSer. No. 07/194,748, filed Jul. 18, 1988, which is now U.S. Pat. No.4,894,367, issued Jan. 16, 1990, which is a divisional application ofSer. No. 07/157,055, filed Feb. 16, 1988, which is now U.S. Pat. No.4,883,816, issued Nov. 28, 1989, which is a divisional application ofSer. No. 06/679,788, filed Dec. 18, 1984, which is now U.S. Pat. No.4,763,942, issued Aug. 8, 1988.

This invention pertains to novel phosphate derivatives, and to methodsof preparation of such compounds. This invention is also concerned withcompositions useful in the treatment of hypertension.

It is estimated that approximately fifteen percent (15%) or more of theadult population in the United States is hypertensive, i.e., havingblood pressures greater than or equal to about 160/95 mm Hg. Of thatpopulation, approximately one-half is unaware of their hypertensivecondition. An untreated hypertensive is at great risk of developingdisabling or fatal left ventricular failure, myocardial infarction,cerebral hemorrhage or infarction, and renal failure at an early age.Hypertension is generally considered the most important risk factorpredisposing to coronary and cerebral atherosclerosis. However, it isbelieved that effective medical control of hypertension will prevent orforestall all complications associated with hypertension and willprolong the life of the hypertensive patient.

Drug therapy for hypertension includes use of diuretics, sympatheticdepressants (e.g., alpha-blockers such as reserpine), vasodilators andfinally blockers of sympathetic transmission at the neuroeffectorjunction (e.g., guanethidine or clonidine).

Among the vasodilators currently employed in hypertension therapy arediazoxide and sodium nitroprusside. Side effects of diazoxide therapyinclude nausea, vomiting, hyperglycemia and tachycardia. Side effectsfrom sodium nitroprusside therapy include nausea, vomiting, agitation,muscular twitching and cutis anserina if blood pressure is reduced toorapidly. Minoxidil is also often used as a vasodilator in hypertensiontherapy. However, the side effects of minoxidil include sodium and waterretention, and hirsutism. Hydralazine, a mild vasodilator, is alsoemployed. Its side effects include headaches, tachycardia, fluidretention, aggravation of angina, gastrointestinal irritation,lupus-like syndrome, drug fever and psychosis.

Acetyl glyceryl ether phosphocholines have been recognized as havingpotent biological activity in platelet activation, and invasoconstriction and vasodilation. See, e.g., U.S. Pat. No. 4,329,302,which issued on May 11, 1982 to Hanahan et al. Such phosphocholines havebeen identified as both a platelet activation factor (PAF) and anantihypertensive polar renomedullary lipid (APRL). See R.L. Wykle etal., FEBS LETTERS, 141: 29-32 (1982); M.L. Blank et al., BIOCHEMICAL ANDBIOPHYSICAL RESEARCH COMMUNICATIONS, 90: 1194-1200 (1979).Antihypertensive phosphocholines do not occur as pre-formed componentsin the body; rather, such phosphocholines are synthesized by certaincells. See. J. Benveniste et al., INT. ARCHS. ALLERGY APPL. IMMUNN., 66(Supp. 1): 121-126 (1981); E.E. Muirhead, HYPERTENSION, 2: 444-464(1980). APRL has been described as being accountable in great measurefor the endocrine-type antihypertensive action exerted by the renalmedullary and the renomedullary interstitial cells. M. L. Blank et al.,ID.

BRIEF SUMMARY OF THE INVENTION

The phosphate derivatives of the present invention have the formula:##STR2## wherein X is selected from one or more of: (a) C₁ -C₂₄ branchedor straight chain alkyl; (b) C₁ -C₂₄ branched or straight chain alkoxy;(c) ##STR3## wherein n and m are integers from zero to 25 and the sum ofn and m is less than or equal to 25; (d) phenyl; (e) substituted phenyl,wherein the substituents are selected from one or more of C₁ -C₂₀branched or straight chain alkyl, C₁ -C₂₀ branched or straight chainalkoxy, halogen, trifluoromethyl, phenyl and substituted phenyl; (f)phenoxy, and (g) substituted phenoxy, wherein the substituents areselected from one or more of the group consisting of C₁ -C₂₀ branched orstraight chain alkyl, halogen, trifluoromethyl, phenyl and substitutedphenyl; Q is selected from the group consisting ##STR4## wherein R₁ isselected from the group consisting of hydrogen, C₁ -C₂₀ branched orstraight chain alkyl, C₁ -C₂₀ branched or straight chain alkoxy and C₁-C₄ branched or straight chain alkylamino and R₃ is C₁ -C₄ alkyl, withthe proviso that when Q is ##STR5## R₁ is C₁ -C₄ branched or straightchain alkyl; wherein T is a bivalent radical selected from the groupconsisting of --(CHR)_(p) --and ##STR6## wherein p is an integer from 1to 15, the moiety --(CHR)_(p) --represents an alkylene chain substitutedat any position with one or more C₁ -C₁₀ alkyl groups or phenyl groups,and the moiety ##STR7## is bound with the oxygen atom attached directlyto the aromatic ring; and wherein Z is selected from the groupconsisting of N⁺ (R₂)₃ and ##STR8## wherein R₂ may be the same ordifferent and is selected from the group consisting of hydrogen and C₁-C₄ branched or straight chain alkyl and q is an integer from 4 to 7.Such derivatives may be in racemic form or as the individual R and Senantiomers.

According to the sequence of reactions outlined in Flowsheet A ahydroxymethyl ketone 2 is treated with an excess of reagents 3a or 3b inan inert solvent such as carbon tetrachloride in the presence of atleast one equivalent of an amine base such as triethylamine giving,after hydrolysis in a buffer such as aqueous sodium acetate, thecompounds of the formula 4.

Compound 4 can readily be reduced to alcohol 5 using sodium borohydridein an alcohol solvent such as ethanol or 1-butanol. Nucleophilicdisplacement of the bromine atom of 5 to give the compound 7 isaccomplished by treatment of 5 with an excess of an amine such as 6a or6b, either in an inert solvent such as acetonitrile, tetrahydrofuran orchloroform at elevated temperatures (about 50°-150° C.) in an enclosedvessel or by heating at about 60° C.-70° C. a solution of 6 and theamine in a mixture of chloroform, 1-propanol, dimethylformamide andwater (about 3:5:5) or other inert solvent mixture. When the compoundsrepresented by structures 6a and 6b are tertiary amines, the products 7of this reaction are quaternary ammonium salts; in these cases it may bedesirable to prepare the internal salt by treatment of anaqueous-alcohol solution of the compound with a suspension of silvercarbonate. The compounds represented by formula 7 can be converted tocompounds 1 of this invention wherein R₁ is a C₁ -C₄ alkyl group by thereaction of 7 with an anhydride 8 in the presence of a base catalystsuch as triethylamine in an inert solvent such as chloroform.

The compounds represented by the formula 7 can be converted to thecompounds 1 of this invention wherein R₁ is a C₁ -C₄ alkoxy group by thereaction of 7 with a pyrocarbonate 10 in the absence of solvent atelevated temperature (about 50°-150° C.).

The compounds represented by the formula 7 can be converted to thecompounds of 1 of this invention wherein R₁ is hydrogen by the reactionof 7 with 97% formic acid at room temperature for about 3 to 7 days.

The compounds represented by the formula 7 can be converted to thecompounds 1 of this invention wherein R₁ is a C₁ -C₄ alkylamino group bytreatment of 7 with an isocyanate 9 in an inert solvent such as tolueneat about 25°-100° C. for about 1 to 7 days.

The preparation of the hydroxymethyl ketone precursors of formula 2 aredescribed in Wissner et al., U.S. Pat. No. 4,640,913, which isincorporated herein by reference and in the prior art. ##STR9##

The preparation of the compounds of this invention encompassed byformula 11 is described hereinbelow in Flowsheet B, wherein R4 is a C₁-C₂₄ branched or straight chain alkyl group or ##STR10## wherein n' andm are integers from zero to 25 and the sum of n' and m is equal to, orless than 25 and n' must be greater than zero; R₁ is a C₁ -C₄ alkylgroup; q, p, Z, T, and R₂ are defined as given hereinabove. The reactionof an equilibrium mixture of 12a and 12b with either reagents 3a or 3bas described hereinabove gives, after hydrolysis in a buffer such assodium acetate solution, the compound 13. The reaction of 13 with theamines 6a or 6b as described above furnishes the compounds of thisinvention represented by formula 11. As described above, compound 11 canbe converted to the corresponding internal salt by treatment with silvercarbonate. The precursor compounds represented by formula 12a and 12bdescribed in Wissner et al., U.S. Pat. No. 4,640,913. ##STR11##

The preparation of compounds of this invention encompassed by formula 14is described hereinbelow in Flowsheet C, wherein X', R₁, T, p, Z, q, andR₂ are defined hereinabove. A mixture of the keto 15a and hemiketal 15bisomers react with either reagents 3a or 3b as described hereinabove tofurnish 16 after hydrolysis in a buffer such as sodium acetate solution.The reaction of 16 with the amines 6a or 6b as described above furnishesthe compounds of this invention represented by formula 14. As describedabove, compound 14 can be converted to the corresponding internal saltby treatment with silver carbonate.

The precursor compounds 15a and 15b are described in Wissner et al.,U.S. Pat. No. 4,640,913. ##STR12##

The compounds of this invention encompassed by formula 17 are preparedas described hereinbelow in Flowsheet D wherein q, p, R₂, R₁ and Z areas defined above. T' is a bivalent radical of the formula -(CHR')_(p) -which represents an alkylene chain substituted at any position with oneor more C₁ -C₁₀ alkyl groups or phenyl groups with the proviso that thecarbon atom substituted with the amine group cannot be substituted witha phenyl group. R₅ is selected from the group consisting of C₁ -C₂₄branched or straight chain alkyl, ##STR13## phenyl, or substitutedphenyl wherein the substituents are selected from one or more of thegroup consisting of C₁ -C₂₀ branched or straight chain alkyl, halogen,trifluoromethyl, phenyl, and substituted phenyl.

Treatment of 18 with reagent 19 as described hereinabove, furnishes,after hydrolysis with a sodium acetate buffer, the compound 20. Thereaction of 20 with amines 6a or 6b as described above gives thecompound 21.

When the compound represented by structures 6a or 6b are tertiaryamines, the products of (21) of this reaction are quaternary ammoniumsalts; in these cases it may be desirable to prepare the internal saltby treatment of an aqueous-alcohol solution of the compound with asuspension of silver carbonate. The benzyl protecting group of 21 can beremoved by catalytic hydrogenation using a catalyst such as palladium oncarbon (5%) to give the alcohol 22.

The compounds represented by the formula 22 can be converted tocompounds 17 of this invention wherein R₁ is an alkyl group by thereaction of 22 with an anhydride 8 in the presence of a base catalystsuch as triethylamine in an inert solvent such as chloroform. Thecompounds represented by the formula 22 can be converted to compounds 17of this invention wherein R₁ is a C₁ -C₄ alkoxy group by the reaction of22 with a pyrocarbonate 10 in the absence of solvent at elevatedtemperature (about 50-150° C.). The compounds represented by the formula22 can be converted to compounds 17 of this invention wherein R₁ ishydrogen by the reaction of 22 with about 97% formic acid at roomtemperature for about 3 to 7 days. The compounds represented by theformula 22 can be converted to compounds 17 of this invention wherein R₁is a C₁ -C₄ alkylamino group by treatment of 22 with an isocyanate 9 inan inert solvent such as toluene at about 25-100° C. for about 1-7 days.

The precursor compounds of formula 18 are described in Wissner et al.,U.S. Pat. No. 4,640,913. ##STR14##

The compounds of this invention encompassed by formula 29 are preparedas outlined hereinbelow in Flowsheet E wherein, R₁, p, q, T and Z are asdefined above and R₇ is selected from the group consisting of C₁ -C₂₄branched or straight chain alkyl, ##STR15## phenyl, or substitutedphenyl wherein the substituents are selected from one or more of thegroup consisting of C₁ -C₂₀ branched or straight chain alkyl, halogentrifluoromethyl, phenyl, and substituted phenyl.

Compound 23 is reacted with 24 in a mixture of pyridine andtetrahydrofuran or other inert solvent to give the compound 25 in whichonly the primary hydroxyl group has reacted. Acylation of 25 with ananhydride 8 using an amine base in an inert solvent gives 26. Thealcohol protecting group of 2 can be removed without acyl migration bypassing a solution of 26, in an inert solvent, through a column packedwith a mixture of silicic acid and boric acid giving the alcohol 27. Thereaction of 27 with reagents 3a or 3b in an inert solvent in thepresence of an amine base gives, after hydrolysis in a buffer such asaqueous sodium acetate, the phosphate 28. The reaction of 28 with amines6a or 6b as described above furnishes the compounds of this inventionrepresented by formula 29. As described above, compound 29 can beconverted to the corresponding internal salt by treatment with silvercarbonate.

The preparation of the precursor diols of formula 23 are described inWissner et al., U.S. Pat. No. 4,640,913. ##STR16##

The preparation of compounds of this invention encompassed by formula 30is described hereinbelow in Flowsheet F wherein R₅, p, q, T, and Z areas defined and R₃ is a C₁ -C₄ alkyl group.

The reaction of 31 with reagent 3a or 3b as described above givescompound 32. The reaction of 32 with alkyl amines 6a or 6b as describedpreviously furnishes the compounds of this invention represented byformula 30.

The precursors of formula 31 are described in Wissner et al., U.S. Pat.No. 4,640,913. ##STR17##

Methods by which the compounds of this invention can be prepared intheir optically active forms are described in detail in Wissner et al.,U.S. Pat. No. 4,640,913 and in the prior art. The reagents 3a and 3bneeded to prepare the compounds of this invention are prepared asoutlined in Flowsheet G wherein the moiety --(CHR)-- is as definedhereinabove. The reaction of a bromoalcohol 33 or a bromophenol 34 withan excess of phosphorousoxychloride in an inert solvent such as carbontetrachloride gives the reagents 3a or 3b, respectively. In some casesit is necessary to catalize this reaction by the addition of oneequivalent of an amine base such as triethylamine. The reagents 3a and3b are useful for the preparation of the antihypertensive compounds ofthis invention. ##STR18##

The compounds of the present invention are active as hypotensive agentsas evidenced by their activity in the following test, the results ofwhich are shown in Table I.

Under ether anesthesia, Weeks type cannulas (Peterson Technics) weresurgically implanted in the abdominal aorta and vena cave ofspontaneously hypertensive rats (Taconic Farms, Germantown, NY) andpassed subcutaneously to the back of the neck where they wereexteriorized. The cannulas were filled with saline, plugged and the ratsreturned to single cages where they were allowed food and water adlibitum.

At least three days following implantation of the cannulas, the ratswere weighed and placed in Broome style restraining cages. The plug wasremoved from the aortic catheter which was connected to an arterialpressure transducer (Statham P23ID) using PE 100 polyethylene tubing anda stepdown connector fabricated from stainless steel hypodermic tubing.Mean arterial blood pressure was obtained by electrical damping of thepulse pressure channel. Heart rate was obtained from a tachographtriggered by the pulse pressure channel. All parameters were monitoredon a Grass physiological recorder (Model 7).

The plug was removed from the vena cava catheter and a PE 20polyethylene tubing extension was added using a piece of stainless steelhypodermic tubing. The other end was terminated with a 27 G needle andone ml syringe.

All drugs were dissolved in saline or a mixture of ethanol and saline(25:75V:V) such that the volume injected intravenously was 0.1 ml/100 gbody weight. All drugs were flushed in with 0.2 ml saline. Bloodpressure was continually monitored both before and after introduction ofthe test compound.

    ______________________________________                                                                        Peak Mean                                                    Dose     No. of  Arterial Blood                                Compound       (ug/kg)  Rats    Pressure (mm,Hg)                              ______________________________________                                        7-(acetyloxy)-4-hydroxy-                                                                     0.3      4       -17.4                                         N,N,N,2-tetramethyl-3,5,-                                                                    1.0      4       -40.2                                         9-trioxa-4-phosphapenta                                                                      3.0      4       -88.8                                         cosan-1-aminium, 4-oxide,                                                                    10.0     4       -96.5                                         hydroxide, inner salt                                                                        30.0     4       -103.4                                        7-(acetyloxy)-4-hydroxy-                                                                     10.0     1       -59.0                                         N,N,N-trimethyl-1-phenyl-                                                     3,5,9-trioxa-4-phosphapen-                                                    tacosan-1-aminium, 4-                                                         oxide, hydroxide, inner                                                       salt                                                                          3-(((2-(acetyloxy)-3-                                                                        0.1      4       -10.4                                         (hexadecyloxy)-propoxyl)-                                                                    0.3      4       -16.3                                         hydroxyphosphinyl)oxy)-                                                                      1.0      4       -37.2                                         N,N,N-trimethyl-benzene                                                                      3.0      4       -83.9                                         methanaminium, hydroxide                                                                     10.0     4       -91.0                                         inner salt                                                                    8-(acetyloxy)-5-hydroxy-                                                                     0.03     4       -16.4                                         N,N,N-trimethyl-4,6,10-                                                                      0.10     4       -36.3                                         trioxa-5-phosphahexacosan-                                                                   0.30     4       -58.6                                         2-aminium, 5-oxide,                                                                          1.0      4       -103.1                                        hydroxide, inner salt                                                                        3.0      4       -118.3                                        7-hydroxy-N,N,N-                                                                             0.03     4        -9.8                                         trimethyl-2-oxo-4-((3-                                                                       0.10     4       -17.6                                         tetradecyl-phenoxy)-                                                                         0.30     4       -78.7                                         methyl)-3,6,8-trioxa-                                                                        1.0      4       -95.9                                         7-phosphaundecan-10-                                                          aminium, 7-oxide                                                              hydroxide inner salt                                                          ______________________________________                                    

When the compounds are employed for the above utility, they may becombined with one or more pharmaceutically acceptable carriers, e.g.,solvents, diluents, and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.5 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing, for example, from about 20 to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 0.05% up to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration and theseverity of the condition being treated. However, in general,satisfactory results are obtained when the compounds of the inventionare administered at a daily dosage of from about 1.0 ug to about 100mg/kg of animal body weight, preferably given in divided doses two tofour times a day, or in sustained release form. For most large animalsthe total daily dosage is from about 500 ug to about 5,000 mg preferablyfrom about 350 ug to 3,500 mg. Dosage forms suitable for internal usecomprise from about 25 ug to 500 mg of the active compound in intimateadmixture with a solid or liquid pharmaceutically acceptable carrier.This dosage regimen may be adjusted to provide the optimal therapeuticresponse. For example, several divided doses may be administered dailyor the dose may be proportionally reduced as indicated by the exigenciesof the therapeutic situation. A decided practical advantage is thatthese active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, e.g., vitamin E,ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the stand-point of easeof preparation and administration are solid composition, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glyercol, liquid polyethyleneglycols, and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations should contain a preservative toprevent the growth of microorganisms.

The pharmaceutical forms suitable for injection use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorgansims such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

In addition to the above utility, some of the compounds of thisinvention (such as 23 of Flowsheet E) are useful for the preparation ofother compounds of this invention.

The invention will be more fully described in conjunction with thefollowing specific examples which are not to be construed as limitingthe scope of the invention.

EXAMPLE 1 1-Bromo-2-propanol

To an ice-cold slurry of 7.79 g of lithium aluminum hydride in 160 ml ofether, under an argon atmosphere, was added dropwise 79 g of1-bromo-2-propanone in 25 ml of ether, maintaining the temperature at5-10° C. After the addition (1.5 hours) the mixture was stirred for 15minutes at 30° C. Water was added dropwise, then 4N sulfuric acid. Theether layer was decanted and saved. The aqueous layer was extracted withthree 100 ml portions of ether. The ether layers were combined, dried,filtered and evaporated on a steam bath. The residue was refrigeratedovernight, then distilled at 46° C., 10 mm giving 21 g of the desiredcompound as an orange red oil.

EXAMPLE 2 Phosporodichloridic acid 2-bromo-1-methylethyl ester

To a solution of 46 g of phosphorous oxychloride in 110 ml of carbontetrachloride was added with stirring 21 g of 1-bromo-2-propanol. Themixture was stirred overnight, the solvent removed and the residueevaporated twice from toluene at 35° C., then evaporated to drynessgiving a dark oil. This oil was distilled on a Kugelrohr at 75° C., 0.3mm giving 16.3 of the desired compounds as a white oil.

EXAMPLE 3 2-Bromo-1-propanol

To 12.31 g of lithium aluminum hydride was added 700 ml of ether. Thismixture was stirred at reflux for 3 hours, then cooled in an ice bath to3° C. A 100 g portion of alpha-bromopropionyl bromide was added dropwiseover 1.25 hours. This mixture was stirred for 2 hours at 0° C., then 35ml of water was added dropwise followed by 225 ml of 4N sulfuric acid.The ether layer was separated and saved. The aqueous layer was extractedtwice with ether. The ether solutions were combined, dried, filtered andconcentrated to a yellow oil. This oil was distilled, 47-48° C., 10 mmgiving 48 g of the desired compound as a white oil.

EXAMPLE 4 Phosphorodichloridic acid-2-bromopropyl ester

To a solution of 42 g of phosphorous oxychloride in 110 ml of carbontetrachloride was added dropwise with stirring a solution of 25 g of2-bromo-1-propanol in 25 ml of carbon tetrachloride. This mixture wasstirred overnight, then taken to dryness, evaporated twice from tolueneand dried. The residue was distilled on a Kugelrohr 75° C., 0.05 mm,giving 26.1 g of the desired compound as a colorless oil.

EXAMPLE 5 Phosphorodichloridic acid-3-bromo-2,2 dimethylpropyl ester

To a solution of 18.35 g of phosphorous oxychloride in 55 ml of carbontetrachloride was added dropwise a solution of3-bromo-2,2-dimethyl-1-propanol in 20 ml of carbon tetrachloride. Thismixture was stirred overnight, evaporated in vacuo, then evaporatedtwice from toluene at 35° C. and dried. The residue was distilled onKugelrohr 100° C., 0.3 mm giving the desired compound as a colorlessoil.

EXAMPLE 6 2-Bromo-2-phenylethanol

To a stirred solution of 25 g of alpha-bromophenylacetic acid in 100 mlof dry tetrahydrofuran was added 151 ml of 1.0M diborane intetrahydrofuran dropwise at 5° C. under argon over 30 minutes. Thismixture was stirred overnight at room temperature, then cooled to 0° C.and 130 ml of tetrahydrofuran:water (1:1) was added dropwise. Themixture was then saturated with potassium carbonate and thetetrahydrofuran removed. The aqueous remainder was extracted three timeswith ether. The extracts were combined and dried. The residue wastriturated with hexane and the solid collected giving the desiredcompound as white needles, mp 38-39° C.

EXAMPLE 7 Phosphorodichloridic acid, 2-bromo-2-phenylethyl ester

To solution of 20 g of 2-bromo-2-phenylethanol in 75 ml of carbontetrachloride was added 30 g of phosophorous oxychloride. This mixturewas stirred on a water bath and 10 g of triethylamine in 40 ml of carbontetrachloride was added dropwise over 30 minutes. This mixture wasstirred at room temperature overnight, then filtered. The filtrate wastaken to dryness, evaporated twice from toluene at 35° C. and thendried, giving 32.1 g of the desired compound as a yellow oil.

EXAMPLE 8

Phosphorodichloridic acid, 3-(bromomethyl)phenyl ester

To mixture of 17 g of m-bromomethylphenol in 150 ml of carbontetrachloride under argon was added a solution of 25.5 g of phosphorousoxychloride in 25 ml of carbon tetrachloride. The solution was cooled ina water bath and a solution of 9.18 g of triethylamine in 35 ml ofcarbon tetrachloride was added dropwise with stirring over 40 minutes.This mixture was stirred in the water bath for 1 hour then overnight atroom temperature, filtered through diatomaceous earth and washed withcarbon tetrachloride. The mother liquor was taken to dryness giving23-29 g of the desired compound as a pale yellow oil.

EXAMPLE 9 2-Bromo-1-methylethylphosphoric acid3-(hexadecyloxy)-2-(phenylmethoxy)propyl ester

To a solution of 4.4 g of phosphorodichloridic acid2-bromo-1-methylethyl ester in 140 ml of carbon tetrachloride, cooled inan ice bath under argon, was added dropwise with stirring 7.09 g oftriethylamine. A solution of 5 g of3-(hexadecyloxy)-2-(phenylmethoxy)-1-propanol in 15 ml of carbontetrachloride was added dropwise. This mixture was stirred for 2 hoursat room temperature then 100 ml of toluene was added and the mixturefiltered through diatomaceous earth and washed with toluene. The motherliquor was taken to dryness. To the residue was 110 ml oftetrahydrofuran and 110 ml of 0.5M aqueous sodium acetate. This mixturewas stirred overnight under argon then the tetrahydrofuran wasevaporated in vacuo. The remaining aqueous phase was acidified with 1Nhydrochloric acid and extracted three times with ether. The etherextracts were combined, washed with saturated aqueous sodium chloride,dried and evaporated giving an oil. This oil was chromatographed onmagnesium silicate as a chloroform solution, eluting with 10% methanolin chloroform and giving 6.58 g of the desired compound.

EXAMPLE 104-Hydroxy-N,N,N,2-tetramethyl-7-(phenylmethoxy)-3,5,9-trioxa-4-phosphapentacosan-1-aminium,4-oxide, hydroxide, inner salt

A solution of 6.49 g of 2-bromo-1-methylethylphosphoric acid3-(hexadecyloxy)-2-(phenylmethoxy)propyl ester in 125 ml of dryacetonitrile, 112 ml of dry chloroform and 50 ml of anhydroustrimethylamine was stirred in an oil bath at reflux temperature for 17hours. The solvents were removed under reduced pressure and the residuedissolved in 65 ml of methanol. A 1.6 g portion of silver carboante wasadded, the mixture stirred for 3 hours, filtered through diatomaceousearth and washed with methanol. The mother liquor was evaporated leavinga glass which was dissolved in 112 ml of chloroform, 125 ml ofacetonitrile and 50 ml of trimethylamine were added and this mixturerefluxed at 65° C. for 24 hours. This mixture was taken to dryness, theresidue dissolved in 70 ml of methanol, 1.6 g of silver carbonate addedand the mixture stirred under argon for 2 days. This mixture wasfiltered through diatomaceous earth, washed with methanol and the motherliquor evaporated giving an oil. This oil was dissolved in chloroformand chromatographed on silica gel, eluting with 10% methanol inchloroform, then 30% methanol in chloroform to remove higher Rfimpurities and then eluting with methanol:chloroform:water (35:65:6).The product fractions were combined, taken to dryness and evaporatedtwice from toluene, giving 932 mg of the desired compound, mp 165-170°C.

EXAMPLE 11 4-Hydroxy-N,N,N,2-tetramethyl-3,5,9-trioxa-4-phosphapentacosan-1-aminium, 4-oxide, hydroxide, inner salt

A solution of 1.6 g of4-hydroxy-N,N,N,2-tetramethyl-7-(phenylmethoxy)-3,5,9-trioxa-4-phosphapentacosan-4-oxide, hydroxide, inner salt in 35 ml of methanol and 35 ml ofglacial acetic acid was hydrogenated with 600 mg of 5% palladium oncarbon in a Parr apparatus at an initial pressure of 25 psi overnight.This mixture was filtered through diatomaceous earth, washed withmethanol, the mother liquor taken to dryness and evaporated twice fromtoluene. The residual glass was triturated with 50 ml of ether, cooledin an ice bath and the solid collected and dried, giving 1.23 g of thedesired compound as a white solid, mp 170° C.

EXAMPLE 127-(Acetyloxy)-4-hydroxy-N,N,N,2-tetramethyl-3,5,9-trioxa-4-phosphapentacosan-1-aminium,4-oxide, hydroxide, inner salt

A solution of 1.1 g of4-hydroxy-N,N,N,2-tetramethyl-3,5,9-trioxa-4-phosphapentacosan-1-aminium,4-oxide, hydroxide, inner salt, 5.24 ml of acetic anhydride, 3.09 ml oftriethylamine and 55 ml of dry chloroform was stirred at reflux (70-75°C.) for 5 hours and then taken to dryness. The residue was evaporatedthree times with toluene giving a glass. This glass was triturated with50 ml of ether, then refrigerated and the solid collected, washed withice cold ether and dried, giving 643 mg of the desired product as awhite solid, mp 145° C.

EXAMPLE 13 3-(Hexadecyloxy)-2-(phenylmethoxy)phosphoric acid,2-bromopropyl ester

To a solution of 4.4 g of phosphorodichloridic acid 2-bromopropyl esterin 140 ml of carbon tetrachloride, cooled in an ice bath under argon,was added with stirring 9.8 ml of triethylamine followed by the dropwiseaddition of a solution of 5 g of3-(hexadecyloxy)-2-(phenylmethoxy)-1-propanol in 20 ml of carbontetrachloride. The mixture was stirred in the ice bath for 30 minutesthen at room temperature for 48 hours, 100 ml of toluene was added andthe mixture was filtered through diatomaceous earth. The filtrate wasevaporated and the residual gum stirred with 110 ml of tetrahydrofuranand 110 ml of 0.5 M aqueous sodium acetate for 2 hours. Thetetrahydrofuran was evaporated and the aqueous remainder acidified with1N hydrochloric acid. This mixture was extracted three times with ether.The ether extracts were combined, washed with saturated aqueous sodiumchloride, dried and evaporated to a syrup. This syrup waschromatographed on magnesium silicate, eluting with chloroform to removethe more mobile impurities then with 10% chloroform to remove the moremobile impurities then with 10% methanol in chloroform, giving 7.2 g ofthe desired compound.

EXAMPLE 145-Hydroxy-N,N,N-trimethyl-8-(phenylmethoxy)-4,6,10-trioxa-5-phosphahexacosan-2-aminium,5-oxide, hydroxide, inner salt

A 25 ml portion of acetonitrile was added to a steel bomb cooled in anice bath. A 7.2 g portion of3-(hexadecyloxy)-2-(phenylmethoxy)phosphoric acid, 2-bromopropyl esterwas dissolved in 25 ml of ice-cold trimethylamine by swirling in an icebath and added to the acetonitrile in the bomb. A 25 ml portion oftrimethylamine and 10 ml of chloroform were added, the bomb was sealedand heated at 60-65° C. overnight. The mixture was cooled, removed fromthe bomb, taken to dryness and dissolved in 25 ml of trimethylamine. A25 ml portion dimethylformamide and 25 ml of trimethylamine were added,the mixture placed in the bomb and heated at 70° C. overnight. Thecontents were cooled, removed from the bomb, taken to near dryness,dissolved in 25 ml of chloroform and 25 ml of methanol and 2.5 ml of 30%hydrogen peroxide added. A 1.62 g portion of silver carbonate was added,the mixture stirred for 2 hours, filtered through diatomaceous earth,washed with methanol and taken to dryness giving a syrup. This syrup wasdissolved in 10% methanol in chloroform and chromatographed on silicagel removing the more mobile impurities by eluting with 10%, 20% andfinally 30% methanol in chloroform. The column was then eluted withchloroform:methanol:water (65:35:6). This eluate was taken to drynessevaporated twice with toluene giving a glass which was triturated withether, giving 1.27 g of the desired compound as a white solid.

EXAMPLE 155,8-Dihydroxy-N,N,N-trimethyl-4,6,10-trioxa-5-phosphahexacosan-2-aminium,5-oxide, hydroxide, inner salt

A solution of 1.7 g of5-hydroxy-N,N,N-trimethyl-8-(phenylmethoxy)-4,6,10-trioxa-5-phosphahexacosan-2-aminium, 5-oxide, hydroxide, inner salt in 40 ml of methanol and 40ml of glacial acetic acid was hydrogenated with 0.7 g of 5% palladium oncarbon in a Parr apparatus overnight at an initial pressure of 25 psi.This mixture was filtered through diatomaceous earth, washed withmethanol, the mother liquor taken to dryness and evaporated twice fromtoluene. The resulting glass was triturated with ether and the solidcollected, giving 1.52 g of the desired compound as a white solid, mp95° C.

EXAMPLE 168-(Acetyloxy)-5-hydroxy-N,N-N-trimethyl-4,6,10-trioxa-5-phosphahexacosan-2-aminium,5-oxide, hydroxide, inner salt

A solution of 1.4 g of5,8-dihydroxy-N,N,N-trimethyl-4,6,10-trioxa-5-phosphahexacosan-2-aminium,5-oxide, hydroxide, inner salt in 70 ml of dry chloroform containing 6.7ml of acetic anhydride and 3.9 ml of triethylamine was stirred at refluxtemperature under argon for 5 hours, then taken to dryness. The residuewas evaporated three times from toluene giving a glass. This glass wastriturated with 50 ml of ether, refrigerated overnight and the solventsremoved. The residue was dissolved in 10 ml of 20% methanol inchloroform and applied to a column filled with silica gel which had beenslurried in 20% methanol in chloroform. The column was eluted with 500ml of 20% methanol in chloroform, then 500 ml of 30% methanol inchloroform to remove mobile impurities and then withchloroform:methanol:water (65:35:6) to remove the product. Fractions8-18 were combined and evaporated. The residue was evaporated twice fromtoluene then triturated with ether, giving 1.20 g of the desired productas a white solid, mp 200-205° C. (dec.).

EXAMPLE 171-(Hexadecyloxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol

To a mixture of 84.5 g of 3-(hexadecyloxy)-1,2-propanediol in 265 ml ofdry pyridine, stirred in an ice bath under nitrogen, was added in asteady stream a solution of 115.5 g of 4-methoxytrityl chloride in 150ml of dry tetrahydrofuran. This mixture was stirred in the ice bath for30 minutes, then at room temperature for 2 hours, then refrigerated at0° C. overnight. The mixture was concentrated to remove the volatilesolvents. The residual solution was dissolved in 400 ml of chloroform,washed twice with 200 ml portions of 10% aqueous sodium bicarbonate andtwice with 200 ml portions of water, dried and evaporated. The residuewas evaporated twice from toluene, taken up in ether, chilled andfiltered. The filtrate was taken to dryness, giving a syrup. A 30 gportion of this syrup was dissolved in petroleum ether andchromatographed on a silica gel column eluting with 20% ether inpetroleum ether. The product fractions 6-20 (200 ml each) were combinedand evaporated, giving 21 g of the desired compound.

EXAMPLE 181-(Hexadecyloxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol,acetate

A solution of 20 g of1-(hexadecyloxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol in 70ml of dry pyridine and 20 ml of acetic anhydride was allowed to stand ina stoppered flask for 24 hours. A 300 ml portion of ice and water wasadded, and the mixture was extracted with two 150 ml portions ofchloroform. The chloroform extracts were combined, washed with two 150ml portions of 10% aqueous sodium bicarbonate, then saturated saline,dried and taken to dryness. The residue was evaporated from toluene,giving a syrup. This syrup was chromatographed on silica gelequilibrated with 120 ml of 15% ether in petroleum ether. The column waseluated with 15% ether in petroleum ether collecting 400 ml. The top 6inches and bottom 16 inches were cut from the column. The remainder ofthe column was cut into thirty-five 1 inch segments.

Cuts 3-20 were combined in ether, then the ether was removed, giving18.4 g of the desired compound as a pale yellow syrup.

EXAMPLE 19 3-(Hexadecyloxy)-1,2-propanediol, 2-acetate

A 200 g portion of silicic acid was suspended five times in distilledwater, with the water decanted each time to remove fine particles.Residual water was filtered off on a sintered glass funnel. The silicicacid was then mixed thoroughly with a hot saturated solution of 20 g ofboric acid in 100 ml of water, then air dried and activated at 120° C.for 24 hours.

A 100 g portion of the activated silicic acid-boric acid mixture wassuspended in 400 ml of petroleum ether and poured onto a 60x3 cm glasscolumn containing 50 ml of petroleum ether. A 10 g portion of1-(hexadecyloxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol,acetate was dissolved in 25 ml of petroleum ether and added to thecolumn. The column was eluted first with 2550 ml of petroleum ether,then with 2825 ml of 5% ether in petroleum ether to remove more mobileimpurities and finally with 3000 ml of 50% ether in petroleum ether,giving 4.54 g of the desired compound as a waxy solid.

EXAMPLE 202-(Acetyloxy)3-(hexadecyloxy)propyl-2-bromo-2-phenylethylphosphoricacid, ester

To a solution of 3.11 g of 3-(hexadecyloxy)-1,2-propanediol, 2-acetatein 40 ml of carbon tetrachloride, cooled in an ice bath under argon wasadded 3.9 g of phosphorodichloridic acid, 2-bromo-2-phenylethyl ester in5 ml of carbon tetrachloride followed by 1.3 g triethylamine in 5 ml ofcarbon tetrachloride. This mixture was stirred in the ice bath for 30minutes, then at room temperature overnight, then filtered and washedwith carbon tetrachloride. The mother liquor was taken to dryness. Theresidue was stirred in 100 ml of tetrahydrofuran and 100 ml of 0.5Maqueous sodium acetate for 2 hours, then the tetrahydrofuran was removedin vacuo. The aqueous remainder was acidified with hydrochloric acid andextracted three times with ether. The ether extracts were combined,washed with saturated aqueous sodium chloride, dried and taken todryness leaving a syrup. This syrup was chromatographed on magnesiumsilicate, eluting the mobile impurities with chloroform and then elutingthe desired compound with 10% methanol in chloroform, giving 911 mg.

EXAMPLE 217-(Acetyloxy)-4-hydroxy-N,N,N-trimethyl-1-phenyl-3,5,9-trioxa-4-phosphapentacosan-1-aminium,4-oxide hydroxide inner salt

To a solution of 911 mg of2-(acetyloxy)-3-(hexadecyloxy)propyl-phosphoric acid,2-bromo-2-phenyl-ethyl ester in 3 ml of dimethylformamide and 2 ml ofchloroform was added 20 ml of trimethylamine. This mixture was heated ina bomb at 100° C. overnight, then cooled, the contents removed and thevolatile solvents evaporated. A 20 ml portion of methanol and 220 mg ofsilver carbonate were added, the mixture stirred for 1.5 hours, filteredthrough diatomaceous earth and washed with methanol. The solvents wereremoved and the syrup dissolved in chloroform and chromatographed onsilica gel which had been slurried in 20% methanol in chloroform. Thecolumn was eluted with 300 ml of 20% methanol in chloroform, then 750 mlof 30% methanol in chloroform to remove mobile impurities, then theproduct was eluted with chloroform:methanol:water (65:35:6). The productfractions 5, 6 and 7 were combined, taken to dryness, evaporated twicefrom toluene, added to ether and refrigerated under argon giving 492 mgof the desired product.

EXAMPLE 22 Phosphoric acid,2-(acetyloxy)-3-(hexadecyloxy)propyl-3-(bromoethyl)phenyl ester

To a solution of 2.86 g of 3-(hexadecyloxy)-1,2-propanediol, 2-acetatein 30 ml of carbon tetrachloride was added 2.43 g ofphosphorodichloridic acid, 3-(bromomethyl)phenyl ester in 5 ml of carbontetrachloride under argon. This solution was stirred in an ice bath anda solution of 809 mg of triethylamine in 5 ml of carbon tetrachloridewas added dropwise. The mixture was then stirred at room temperature for2 hours, toluene was added and the mixture filtered and washed withtoluene. The mother liquor was taken to dryness. To the residual oil wasadded 40 ml of tetrahydrofurean and 40 ml of 0.5M aqueous sodiumacetate. This mixture was stirred for 24 hours, placed in a freezer,concentrated in vacuo to remove the tetrahydrofuran and acidified withcold 0.5N hydrochloric acid. This mixture was extracted twice withether. The extracts were combined, washed with saturated sodium chloridesolution, dried and evaporated giving a syrup. This syrup waschromatographed on magnesium silicate, eluting first with chloroform toremove mobile impurities, then with 10% methanol in chloroform. Cuts 6,7 and 8 where combined and evaporated, giving 2.2 g of the desiredcompound.

EXAMPLE 23 3-(((2-(Acetyloxy)-3-(hexadecyloxy)propoxy)hydroxyphosphinyl)oxy)-N,N,N-trimethylbenzenemethanaminium, hydroxide inner salt

A 2.2 g portion of phosphoric acid,2-(acetyloxy)-3-(hexadecyloxy)propyl-3-(bromomethyl)phenyl ester wasdissolved in 4 ml of dry dimethylformamide. A 15 ml portion of 33%trimethylamine in acetonitrile was added, the mixture was stirred for 20minutes, then 10 ml of 33% trimethylamine in acetonitrile was added andthe mixture was stirred in a 45° C. water bath for 20 minutes. Themixture was then stoppered and refrigerated. The solvents were removedand the residue triturated with ether giving a white solid. The solidwas dissolved in 10 ml of chloroform:methanol:water (65:35:3) andchromatographed on silica gel which was wet with the same solventsystem. The column was developed with the same solvent system. Theeluate was evaporated to dryness, then evaporated twice from toluene,taken up to 20 of methanol and filtered through diatomaceous earth. Thefiltrate was evaporated and the residue triturated with ether andrefrigerated for 48 hours. The solid was collected, giving 1.196 g ofthe desired product as a white solid.

EXAMPLE 241-((4-Methoxyl)diphenylmethoxy)-3-(3-tetradecylphenoxy)-2-propanol

A solution of 25.94 g of 4-methoxytrityl chloride in 15 ml of drytetrahydrofuran was added to a stirred solution of 21.84 g of3-(3-tetradecylphenoxy)-1,2-propanediol in 40 ml of pyridine underargon. This mixture was stirred overnight, the solvents removed underreduced pressure and the residue dissolved in chloroform. This solutionwas washed with saturated aqueous sodium bicarbonate, then water, driedand evaporated, giving 34.3 g of the desired compound.

EXAMPLE 251-((4-methoxyphenyl)diphenylmethoxy)-3-(3-tetradecylphenoxy)-2-propanol,acetate

A mixture of 63.6 g of1-((4-methoxyphenyl)diphenylmethoxy)-3-(3-tetradecylphenoxy)-2-propanol,60 ml of acetic anhydride and 200 ml of pyridine was stirred for 72hours, then poured onto ice and extracted several times with chloroform.The chloroform extracts were combined, washed three times with saturatedaqueous sodium bicarbonate, then with water, dried and the solventremoved under reduced pressure. The residue was evaporated three timesfrom 200 ml portions of toluene, giving 62.6 g of the desired compound.

EXAMPLE 26 3-(3-Tetradecylphenoxy)-1,2-propanediol, 2-acetate

A silicic acid-boric acid column was prepared as described in Example 19using 320 g of the powder.

A 30 g portion of1-((4-methoxyphenyl)diphenylmethoxy)-3-(3-tetradecylphenoxy)-2-propanol,acetate was dissolved in 30 ml of petroleum ether and introduced to thecolumn. The column was eluted with 3 liters of petroleum ether, then 4.5liters of petroleum ether:ether (95:5) to remove impurities and thenwith petroleum ether:ether (3:1) to elute the desired compound, giving14.3 g.

EXAMPLE 27 2-(Acetyloxy)-3-(3-tetradecylphenoxy)propyl phosphoric acid,2-bromopropyl ester

A mixture of 812 mg of 3-(3-tetradecylphenoxy)-1,2-propanediol,2-acetate, 610 mg of phosphorodichloridic acid 2-bromopropyl ester and243 mg of triethylamine in 30 ml of carbon tetrachloride was stirredunder argon for 2 hours, then filtered through diatomaceous earth andthe solvent removed under reduced pressure. The residue was dissolved in15 ml of tetrahydrofuran and 15 ml of 0.5M aqueous sodium acetate wasadded. The mixture was stirred for 1 hour, then extracted several timeswith ethyl acetate. The organic extracts were combined, dried andevaporated. The residue was purified by column chromatography onmagnesium silicate eluting impurities with chloroform, thenchloroform:methanol (9:1), then the desired compound withchloroform:methanol (7:3), giving 900 mg.

EXAMPLE 287-Hydroxy-N,N,N-trimethyl-2-oxo-4-((3-tetradecylphenoxy)methyl)3,6,8-trioxa-7-phosphaundecan-10-aminium,7-oxide, hydroxide, inner salt

A mixture of 606 mg of 2-(acetyloxy)-3-(3-tetradecylphenoxy)propylphosphoric acid, 2-bromopropyl ester, 10 ml of trimethylamine, 5 ml ofacetonitrile and 5 ml of chloroform was heated in a steel bomb at75°-90° C. for 24 hours, then cooled and the solvents removed. Theresidue was purified on a silica gel column, eluting impurities withchloroform:methanol (9:1), then 1:1) and then eluting the desiredproduct with chloroform:methanol:water (6:4:05).

EXAMPLE 29 4-Tetradecylphenol, acetate

A mixture of 290 mg of 4-tetradecylphenol, 2ml of acetic acid and 5 mlof pyridine was stirred for 24 hours, then diluted with ether and washedwith aqueous sodium bicarbonate. The mixture was dried and the solventsremoved, giving 256 mg of the desired compound, mp 32°-34° C.

EXAMPLE 30 1-(2-Hydroxy-5-tetradecylphenol)ethanone

A 900 mg portion of 4-tetradecylphenol, acetate was heated at 70° C.under argon and 720 mg of aluminum trichloride was added portionwise.After 2 hours the temperature was raised to 120° C. and the mixture washeated at this temperature for 45 minutes. The mixture was then cooled,diluted with chloroform, washed with 50% aqueous hydrochloric acid thenwater and dried. The solvents were removed and the residuerecrystallized from ether-methanol, giving 850 mg of the desiredcompound, mp 38.5°-39.5° C.

EXAMPLE 31 2-Ethyl-4-tetradecylphenol

A mixture of 23 g of 1-(2-hydroxy-5-tetradecylphenol)ethanone, 5 g of 5%palladium on carbon catalyst, 10 ml of concentrated hydrochloric acid,100 ml of water and 100 ml of glacial acetic acid was warmed to 50° andthen hydrogenated in a Parr apparatus for 24 hours. This mixture wasfiltered, the solvent removed and the residue dissolved in ether. Theether solution was washed with water, then a small amount of diluteaqueous sodium bicarbonate and dried. The residue was purified by HPLC,giving 16 g of the desired compound, mp 45.5°-46.5° C.

EXAMPLE 324-((2-Ethyl-4-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane

To a suspension of 2.53 g of prewashed 50% sodium hydride in 130 ml ofdimethylformamide was added dropwise a solution of 11.99 g of2-ethyl-4-tetradecylphenol in dimethylformamide. The resultingsuspension was heated at 80° C for 1/2 hour, then allowed to cool and10.29 g the mesylate of solketal was added. The mixture was heated atreflux for 3 hours, then cooled quenched slowly with water and extractedseveral times with ether. The ether extracts were combine, washed withbrine, dried and the solvents evaporated, giving 16.1 g of the desiredcompound, mp 34°-38° C.

Example 33 3-Ethyl-4-tetradecylphenoxy)-1,2-propanediol

A mixture of 15.55 g of4-((2-ethyl-4-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane, 10ml of 5% hydrochloric acid and 300 ml of tetrahydrofuran was heated atreflux for 4 hours, then cooled and 1/2 of the solvent evaporated atreduced pressure. The remainder was diluted with ethyl acetate, washedwith aqueous sodium bicarbonate, dried and the solvents evaporated. Theresidue was chromatographed on silica gel, eluting first withhexane:ethyl acetate (8:1), then (4:1), giving 12.1 g of the desiredcompound, mp 55°-56° C.

EXAMPLE 341-(2-Ethyl-4-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol

A mixture of 11.68 g of 3-(2-ethyl-4-tetradecylphenoxy)-1,2-propanediol,14.95 g of trityl chloride and ml pyridine was stirred for 72 hours,then diluted with chloroform, washed with two 100 ml portions of aqueoussodium bicarbonate, then water and dried. The solvents were evaporatedunder reduced pressure and the residue evaporated with toluene. Thisresidue was then diluted with hexane and the solid which formedcollected giving 18 g of the desired compound.

EXAMPLE 352-Ethyl-1(2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy)-4-tetradecylbenzen

To a suspension of 2.016 g of prewashed sodium hydride in 125 ml ofdimethylformamide was added dropwise a solution of 17.75 g of1-(2-ethyl-4-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol in 125ml of dimethylformamide. This mixture was stirred 15 minutes, then 7.198g of benzyl bromide was added and stirring was continued for anadditional 3 hours. The reaction mixture was quenched slowly with waterand then extracted several times with ether. The ether extracts werecombined, washed with water, dried and the solvent evaporated, giving19.9 g of the desired compound.

EXAMPLE 36 2-(Phenylmethoxy)-3-(2-ethyl-4-tetradecylphenoxy)-1-propanol

A stream of dry hydrogen chloride gas was bubbled into 200 ml ofchloroform at 0° C. for 20 minutes, then a solution of 19.548 g of2-ethyl-1-(2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy)-4-tetradecylbenzenein 100 ml of chloroform was added slowly. This solution was stirred at0° C. for 2.5 hours, then solid sodium bicarbonate was added andstirring continued for 1 hour. The mixture was filtered and thechloroform removed under reduced pressure. The residue was diluted withether, washed with saturated aqueous sodium bicarbonate, dried and thesolvent removed. The residue was chromatographed on silica gel, elutingwith hexane:ether (18:1), giving 12.5 g of the desired compound, mp46°-47° C.

EXAMPLE 37 Hexanoic acid, 4-tetradecylphenol ester

A mixture of 43.5 g of 4-tetradecylphenol, 34.8 g of hexanoic anhydrideand 120 ml of pyridine was stirred for 3 days, then quenched with waterand extracted with chloroform. The chloroform extract was washed severaltimes with aqueous sodium bicarbonate, dried and the solvents removed.The residue was recrystallized from ether-methanol, giving 53.2 g of thedesired compound.

EXAMPLE 38 1-(2-Hydroxy-5-tetradecylphenol)-1-hexanone

To a melted liquid of 38.8 g of hexanoic acid, 4-tetradecylphenol esterat 80°-95° C. was added 26.67 g of aluminum chloride in small portionsover a period of 2 hours. This mixture was heated for an additionalhour, then allowed to cool, diluted with ether and poured onto icecontaining 10 ml of concentrated hydrochloric acid. The organic layerwas washed with water, dried and the solvent evaporated. The residue waschromatographed on silica gel, eluting with hexane:ethyl acetate (50:1),giving 33 g of the desired compound, mp 41°-42° C.

EXAMPLE 39 2-Hexyl-4-tetradecylphenol

A mixture of 31.04 g of 1-(2-hydroxy-5-tetradecylphenol)-1-hexanone, 8.4g of 5% palladium on carbon, 5 ml of concentrated hydrochloric acid, 95ml of water and 100 ml of glacial acetic acid was hydrogenated in a Parrapparatus for 16 hours, then filtered and the solvents removed. Theresidue was chromatographed on silica gel, eluting with hexane:ethylacetate (40:1), giving 12.3 g of the desired compound.

EXAMPLE 40 4-((2-Hexyl-4-tetradecylphenoxy)methyl)-2,2dimethyl-1,3-dioxolane

To a suspension of 2.27 g of prewashed 50% sodium hydride in 65 ml ofdimethylformamide was added dropwise a solution of 11.78 g of2-hexyl-4-tetradecylphenol in 65 ml of dimethylformamide. This mixturewas heated for 1/2 hour, then 8.61 g of the mesylate of solketal wasadded. The mixture was heated at reflux for 3 hours, cooled, quenchedcarefully with water and extracted several times with ether. The etherextracts were combined, dried and the solvent evaporated, giving 15 g ofthe desired compound.

EXAMPLE 41 3-(2-Hexyl-4-tetradecylphenoxy)-1,2-propanediol

A mixture of 13.6 g of4-((2-hexyl-4-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane, 10ml of 5% hydrochloric acid and 250 ml of tetrahydrofuran was heated atreflux for 4 hours, then allowed to cool and the tetrahydrofuran removedunder reduced pressure. The mixture was then extracted several timeswith ethyl acetate. The organic extracts were combined, washed withaqueous sodium bicarbonate, dried and the solvent evaporated, giving12.3 g of the desired compound.

EXAMPLE 421-(2-Hexyl-4-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol

A mixture of 11.64 g of 3-(2-hexyl-4-tetradecylphenoxy)-1,2-propanediol,12.32 g of trityl chloride and 40 ml of pyridine was stirred for 24hours, then diluted with chloroform, washed with aqueous sodiumbicarbonate, water, dried and the solvents evaporated under reducedpressure. The residue was coevaporated with toluene giving 14.6 g of thedesired compound.

EXAMPLE 432-Hexyl-1-(2-phenylmethoxy)-3-(triphenylmethoxy)propoxy)-4-tetradecylbenzene

A solution of 12.21 g of1-(2-hexyl-4-tetradecylphenoxy)-3-triphenylmethoxy)-2-propanol in 50 mlof dimethylformamide was added to a suspension of 1.27 g of prewashed50% sodium hydride in 50 ml of dimethylformamide. This mixture wasstirred for 15 minutes, then 3.94 g of benzyl bromide was added andstirring continued for 3 hours. This mixture was diluted with ether,washed with water and brine, dried and the solvent evaporated, giving13.08 g of the desired compound.

EXAMPLE 44 3-(2-Hexyl-4-tetradecylphenoxy)-2-(phenylmethoxy)-1-propanol

A solution of 11.9 g of2-hexyl-1-(2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy)-4-tetradecylbenzenein 250 ml of chloroform was cooled to 0° C. A stream of dry hydrogenchloride gas was bubbled into the solution for 1/2 hour, then themixture was stirred for 2 hours at 0° C. Solid sodium bicarbonate wasadded, the mixture stirred for 3 hours, then filtered and the chloroformevaporated. The residue was dissolved in ether, washed with aqueoussodium bicarbonate, dried and the residue chromatographed on silica gel.The column was eluted with hexane:ethyl acetate, giving 5.8 g of thedesired compound, mp 32°-33° C.

EXAMPLE 45 Hexanoic acid, 3-tetradecylphenol ester

To a solution of 10.73 g of 3-tetradecylphenol in 30 ml of pyridine wasadded 8.02 g of hexanoic anhydride. The mixture was stirred 24 hours,then diluted with chloroform, washed with water, then saturated aqueoussodium bicarbonate, dried and the solvent evaporated, giving 14.01 g ofthe desired compound.

Example 46 1-(2-Hydroxy-4-tetradecylphenol)-1-hexanone

A 14.28 g portion of hexanonic acid, 3-tetradecylphenol ester was heatedto 90°-100° C., then 9.81 g of aluminum chloride was added in portionsover 2 hours. Heating was continued for an additional hour, then themixture was allowed to cool, diluted with ether and poured onto amixture of ice and concentrated hydrochloric acid. The ether layer waswashed with water, then dried and the solvent removed, giving 7 g of thedesired compound, mp 44°-45° C.

Example 47 2-Hexyl-5-tetradecylphenol

A mixture of 16.99 g of 1-(2-hydroxy-4-tetradecylphenol)-1-hexanone, 4 gof 5% palladium on carbon catalyst, 100 ml of glacial acetic acid and 50ml of methanol was hydrogenated in a Parr apparatus for 24 hours. Themixture was filtered, the solvents removed and the residue dissolved inether, washed with water and dried. This crude material waschromatographed on silica gel, eluting with hexane:ethyl acetate (10:1),giving 15.3 g of the desired product, mp 43°-45° C.

EXAMPLE 483-((2-Hexyl-5-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane

To a suspension of 2.77 g of prewashed sodium hydride in 75 ml ofdimethylformamide was added dropwise a solution of 14.4 g of2-hexyl-5-tetradecylphenol in 75 ml of dimethylformamide. This mixturewas refluxed for 1/2 hour, then 10.5 g of the mesylate of solketal wasadded and the mixture was refluxed for an additional 3 hours. Aftercooling the mixture was quenched slowly with water and then extractedseveral times with ether. The ether extracts were combined, washed withwater, brine, dried and evaporated, giving 18 g of the desired compound.

EXAMPLE 49 3-(2-Hexyl-5-tetradecylphenoxy)1,2-propanediol

A mixture of 17.47 g of3-((2-hexyl-5-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane, 10ml of 5% hydrochloric acid and 150 ml of tetrahydrofuran was refluxedfor 5 hours, then cooled and the tetrahydrofuran removed under reducedpressure. The remainder was extracted several times with ethyl acetate.The organic extracts were combined, washed with aqueous sodiumbicarbonate, dried and solvent evaporated. The residue waschromatographed on silica gel, eluting with hexane:ethyl acetate, giving13.6 g of the desired compound, mp 46°-47° C.

Example 501-(2-Hexyl-5-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol

A mixture of 12.77 g of 3-(2-hexyl-5-tetradecylphenoxy)-1,2-propanediol,13.5 g of trityl chloride and 40 ml of pyridine was stirred for 24hours, then diluted with chloroform, washed with aqueous sodiumbicarbonate, water and dried. This crude material was chromatographed onsilica gel, eluting with 17% ethyl acetate in hexane, giving 14 g of thedesired compound.

EXAMPLE 511-Hexyl-2-(2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy)-4-tetradecylbenzene

A 13.8 g portion of1-(2-hexyl-5-tetradecylphenoxy)-3-(triphenylmethoxy)-2-propanol in 40 mlof dimethylformamide was added dropwise to a suspension of 14.5 g ofprewashed 50% sodium hydride in 40 ml of dimethylformamide and themixture was stirred 15 minutes. A 4.45 g portion of benzyl bromide wasadded and the mixture was stirred an additional 3 hours. This mixturewas quenched slowly with water and then extracted several times withether. The ether extracts were combined, washed with water, brine, driedand evaporated, giving 15 g of the desired compound.

EXAMPLE 52 3-(2-Hexyl-5-tetradecylphenoxy)-2-(phenylmethoxy)-1-propanol

A 500 ml portion of chloroform was cooled to 0° C. and dry hydrogenchloride gas was bubbled in for 10 minutes, then an ice-cold solution of14.43 g of1-hexyl-2-(2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy)-4-tetradecylbenzenein chloroform was added. The mixture was stirred at 0° C. for 1.5 hours,then solid sodium bicarbonate was added and stirring continued for 1hour at room temperature. The mixture was filtered, the solvent removedunder reduced pressure and the residue purified by chromatography,eluting impurities with 1% ethyl acetate in hexane, then eluting thedesired compound in ethyl acetate:hexane (1:8), giving 8.8 g of thedesired compound.

EXAMPLE 53 3-Tetradecylpropanol acetate

A mixture of 18.85 g of 3-tetradecylphenol, 20 ml of acetic anhydrideand 60 ml of pyridine was stirred for 16 hours, then diluted withchloroform, washed with aqueous sodium bicarbonate, dried and thesolvent removed by evaporation with toluene, giving 21 g of the desiredcompound.

EXAMPLE 54 1-(2-Hydroxy-4-tetradecylphenol)ethanone

A 20 g portion of 3-tetradecylphenol, acetate was heated at 110° C. and8.4 g of aluminum chloride was added in portions over a 3 hour period.The mixture was allowed to cool, then diluted with ether, poured ontoice containing 10 ml of concentrated hydrochloric acid and extractedseveral times with ether. The ether extracts were combined, washed withwater, brine and dried. The crude material was chromatographed on silicagel, eluting with hexane:ethyl acetate (50:1), giving 15.8 g of thedesired compound, mp 45°-46° C.

EXAMPLE 55 2-Ethyl-5-tetradecylphenol

A 15.6 g portion of 1-(2-hydroxy-4-tetradecylphenol)-ethanone was heatedin a mixture of 120 ml of acetic acid and 30 ml of methanol untilsolution was complete. A 4 g portion of 5% palladium on carbon was addedand the mixture was hydrogenated in a Parr apparatus for 18 hours. Themixture was then filtered through diatomaceous earth and the solventsremoved under reduced pressure, giving 14.5 g of the desired compound,mp 59°-60° C.

EXAMPLE 564-((2-Ethyl-5-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane-1,3-dioxolane

A solution of 11.29 g of 2-ethyl-5-tetradecylphenol in 50 ml ofdimethylformamide was added dropwise to a suspension of 2.56 g ofprewashed 50% sodium hydride in 50 ml of dimethylformamide. Afterbubbling ceased the mixture was heated for 1/2 hour, then 11.13 g of themesylate of solketal was added. This mixture was refluxed for 3 hours,then allowed to cool, diluted with ether, washed with water, dried andthe solvents evaporated, giving 15 g of the desired compound.

EXAMPLE 57 3-(2-Ethyl-5-tetradecylphenoxy)-1,2-propanediol

A mixture of 14.2 g of4-((2-ethyl-5-tetradecylphenoxy)methyl)-2,2-dimethyl-1,3-dioxolane, 50ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran was heated atreflux for 8 hours, then allowed to cool and the tetrahydrofuran removedunder reduced pressure. Ethyl acetate was added, the mixture washed withwater, dried and the solvents removed. The residue was chromatographedon silica gel, eluting impurities with hexane:ethyl acetate (16:1) andthe (4:1) to elute the desired compound, giving 11 g, 55.5°-56.5° C.

EXAMPLE 581-(2-Ethyl-5-tetradecylphenoxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanol

A mixture of 10.58 g of 3-(2-ethyl-5-tetradecylphenoxy)-1,2-propanediol,9.59 g of p-methoxytrityl chloride, 20 ml of pyridine and 10 ml oftetrahydrofuran was stirred for 3 days. The tetrahydrofuran was removedunder reduced pressure. The residue was diluted with chloroform, washedseveral times with saturated aqueous sodium bicarbonate, dried, filteredand the solvent evaporated. The residue was coevaporated with toluene,giving 17.65 g of the desired compound.

EXAMPLE 591-Ethyl-2-(3-((4-methoxyphenyl)diphenylmethoxy)-2-(phenylmethoxy)propoxy)-4-tetradecylbenzene

To a suspension of 1.87 g of prewashed 50% sodium hydride in 50 ml ofdimethylformamide was added a solution of 17.26 g of1-(2-ethyl-5-tetradecylphenoxy)-3-((4-methoxyphenyl)diphenylmethoxy)-2-propanolin 50 ml of dimethylformamide. This mixture was stirred for 15 minutes,then 5.79 g of benzyl bromide was added. This mixture was stirred 3hours, quenched slowly with water and extracted several times withether. The ether extracts were combined, washed with water, dried andthe solvent removed, giving 19.1 g of the desired compound.

EXAMPLE 60 3-(2-Ethyl-5-tetradecylphenoxy)2-(phenylmethoxy)-1-propanol

A stream of dry hydrogen chloride gas was bubbled into 500 ml ofchloroform at 0° C. for 1 hour, then a cooled solution of 18.85 g of1-ethyl-2-(3-((4-methoxyphenyl)diphenylmethoxy)-2-(phenylmethoxy)propoxy)-4-tetradecylbenzenein chloroform was added. The mixture was stirred 3 hours, then drysodium bicarbonate was added. This mixture was stirred for 1 hour,filtered and the solvent removed. The residue was purified on silicagel, eluting with hexane:ethyl acetate (8:1), giving 10.01 g of thedesired compound.

Included in this invention are compounds of the formula: ##STR19##wherein R" is a C₂ -C₂₀ alkyl group, R₁ ^(") is a C₁ to C₄ alkyl group,y is an integer from 2 to 10 and J⁻ is a pharmacologically acceptableanion. The compounds represented by the above formula are prepared asdescribed hereinbelow in Flowsheet H.

According to the reactions outlined hereinbelow in Flowsheet Halkylation of an alcohol 37 with chloroacetic acid is accomplished bythe prior formation of the sodium salt of the acid by addition to asuspension of excess sodium hydride in toluene; addition of the alcoholand refluxing furnishes, after work up, the carboxylic acid 38. Thereaction of 38 with an excess of vinyl lithium in dimethoxyethane givesthe unsaturated ketone 39. Compound 40 is prepared in a one pot reactioninvolving a sequential Michael addition and reduction. Thus, addition ofan excess of a N,N-dimethylamino thiol 41 to an ethanol solution of 39followed by the portionwise addition of sodium borohydride gives 40.Acylation of 40 with an anhydride and triethylamine gives the acylderivative 42. The amino group of 42 is quarternized to give 43 by thereaction of an etheral solution of 42 with one equivalent of methyliodide at room temperature for one to five days. Finally, oxidation of43 to the sulfone is accomplished with 40% peracetic acid in methylenechloride at room temperature to give, after treatment with the desiredanion exchange resin, the compounds of the invention of formula 44.##STR20##

EXAMPLE 61 1-(Hexadecyloxy)acetic acid

To a suspension of 44.5 g of washed (hexane) 50% sodium hydride mineraloil dispersion in 500 ml of toluene was added with mechanical stirringunder argon a solution of 46.8 g of chloroacetic acid in 200 ml oftoluene over 1 hour. A solution of 100 g of 1-hexadecanol in 200 ml oftoluene was then added over 15 minutes. The mixture was stirred atreflux 40 hours, cooled to room temperature, and acidified with dilutehydrochloric acid. The mixture was heated until all solid dissolved. Thehot organic layer was dried over magnesium sulfate and cooled giving84.5 g of product as a colorless solid: mp 64°-66° C.

EXAMPLE 62 1-(Hexadecyloxy)-3-buten-2-one

To a solution of 88 g of 1-(hexadecyloxy)acetic acid in 800 ml of DMEwas added dropwise under argon with stirring at 0° C., 280 ml of 2.3Mvinyl lithium in THF. The mixture was stirred at 40° C. overnight. TLCof an aliquot quenched with dilute hydrochloric acid indicated that somestarting material remained unreacted. The solution was cooled to roomtemperature and another 180 ml of vinyl lithium solution was added. Themixture was maintained at 40° C. for 18 hours. The mixture was cooled toroom temperature and pumped into dilute hydrochloric acid with icecooling under argon. The mixture was saturated with sodium chloride andthe organic layer was separated. The aqueous layer was extracted withether. The combined organic solutions were dried over magnesium sulfateand the solvent was removed. The product was chromatographed viapreparative HPLC (hexane-ether) giving 26.7 g of a white solid. TLCshowed a major component which gave a yellow spot on treatment with2,4-dinitrophenylhydrazine spray, and a minor component with slightlylower retention time which did not react with the reagent spray.Obtained in this manner the product was used in the next step withoutadditional purification.

EXAMPLE 63 4-((3-Dimethylamino)propyl)thio)-1-(hexadecyloxy)-2-butanol

A solution of 26.5 g of 1-(hexadecyloxy)-3-buten-2-one in 200 ml ofethanol was warmed on a steam bath until all solid dissolved. To thesolution was added 26.9 g of 3-N,N,-dimethylaminopropanthiol. Afterstirring 1 hour, 3.23 g of solid sodium borohydride was addedportionwise over 30 minutes. After stirring an additional 11/2 hours,the solution was poured into water and extracted with ether. The ethersolution was dried over magnesium sulfate. Solvent and excess reagentwere removed at reduced pressure. The residue was chromatographed onsilica gel via preparative HPLC eluting with chloroform-methanol (9:1)giving 13.7 g of product as a colorless solid: mp 30°-32° C.

EXAMPLE 64 4-((3-(Dimethylamino)propyl)thio)-1-(hexadecyloxy)-2-butanol,acetate

A solution of 12.5 g of4-((3-(dimethylamino)-propyl)thio)-1-(hexadecyloxy)-2-butanol, 73.9 g ofacetic anhydride, and 29.3 g of triethylamine in 700 ml of chloroformwas refluxed for 35 hours. Solvent and excess anhydride were removed atreduced pressure. TLC (silica gel, chloroform-methanol-water 70:30:5)indicated that some unreacted starting material remained; 40 ml ofacetic anhydride and 0.2 g of sodium acetate were added and the mixturewas refluxed for 15 minutes. The excess anhydride was removed at reducedpressure at 40°-60° C. The residue was dissolved in ether-methanol,treated with activated charcoal and filtered through a pad of silicagel. Solvent was removed giving 13.2 g of product as a yellow oil.

EXAMPLE 653-((3-(Acetyloxy)-4-(hexadecyloxy)-butyl)thio)-N,N,N-trimethyl-1-propanaminium,Iodide

A solution of 12.0 g of4-((3-dimethylamino)propyl]thio-1-(hexadecyloxy)-2-butanol, acetate and3.59 g of methyl iodide in 200 ml of ether was allowed to stand at roomtemperature for 5 days. Solid was collected and washed with ether giving11.3 g of product as a colorless powder.

EXAMPLE 663-((3-(Acetyloxy)-4-(hexadecyloxy)butyl)sulfonyl)-N,N,N-trimethyl-1-propanaminiumchloride

To a solution of 3.5 g of 3-((3-(acetyloxy)-4-(hexadecyloxy)-butyl)thio)-N,N,N-trimethyl-1-propanaminium iodide in 150 ml of dichloromethane wasadded 9.0 g of 40% peracetic acid. After standing overnight, a saturatedsolution of sodium bisulfite was added until the iodine colordisappeared. Solvent was removed. Ethanol and then dichloromethane wereadded and then evaporated to remove the last traces of water. Theresidue was mixed with dichloromethane-methanol (1:2). The solution wasstirred with 100 g of chloride ion exchange resin (Bio-Rad AGI-X2) for10 minutes. The mixture was filtered and the filtrate was stirred withanother 50 g of resin. The mixture was filtered and solvent was removed.The residue was triturated with ether and 2.65 g of product wascollected as a white powder which did not have a well defined meltingpoint.

Compounds of formula 43 are useful as inhibitors of phospholipase A₂ inthe treatment of asthma and as antiinflammatories. Preferably, they areadministered systemically, i.e. orally. The presently preferred dosagefor a human subject ranges from about 0.1 mg/kg to about 10 mg/kg individed doses daily.

Compounds of formula 44 are also useful as antihypertensive agents. Forexample, in the antihypertension assay describe above,3-((3-(acetyloxy)-4-(hexadecyloxy)butyl)sulfonyl)N,N,N-trimethyl-1-propanaminiumchloride reduced the blood pressure in the spontaneously hypertensiverat 20 mm Hg at a dose of 10 mg/kg (iv).

EXAMPLE 67

4-((3-(Dimethylamino)propyl)thio)-1-(hexadecyloxy)-2-butanol, acetatewas prepared by the method of Example 64 as a 1 mg/ml solution inmethanol. Inhibition of phospholipase A₂ activity was measured by aradiochemical assay in which labeled synthetic phosphatidylcholinesubstrate is converted by porcine pancreatic PLA₂ to free radiolabeledarachidonate and lyso phosphatidyl choline. In the assay, radiolabeledarachidonate is extracted from the reaction mixture and separated fromunreacted substrate by column or thin layer chromatography. Theradioactivity (cpm) in samples is quantified in liquids scintillationcounting.

Labeled substrate (1-stearyl-2-3H-arachidonyl phosphatidylcholine)(Amersham, sp. act. 84 Ci/mmole, 0.025 to 0.2 uCi/assay tube) andunlabeled substrates (Avanti) in sufficient quantity to give 20,000 to50,000 cpm and 10 uM to 1,000 uM final concentration/assay tube) weredried under a stream of nitrogen. The combined substrate was thenredissolved in 0.1M Tris-HCl buffer, pH 9.0, containing 10 mM calciumchloride and 10 mM sodium taurocholate detergent. The mixture wassonicated for 10 to 30 seconds in a Kontes Sonifier to yield ahomogeneous dispersion. The "mixed" micellar substrate was clear. Analiquot was reserved for a cpm count (total substrate). The totalreaction volume was 500 ul; siliconized glassware or plasticware wasused throughout. Porcine pancreatic phospholipase A₂ enzyme (Sigma, sp.act. σ690 U/mg protein and preferably 900 U/mg protein) was diluted1:750 or 1:1000 in 0.1M Tris-HCl buffer, pH 9.0 (without Ca⁺⁺ anddetergent).

The test compound was diluted appropriately in phosphate bufferedsaline. 10 ul aliquots of the stock solution were either incubated withenzyme in buffer in the absence of Ca⁺⁺ detergent or were blown under N₂stream with the substrate prior to the addition of buffer. The substrateand buffer were kept on ice until the reaction was started by theaddition of enzyme (preincubated with test compound or diluent, or freshenzyme) to the substrate dispersion in buffer.

Samples (600 ul) were extracted with 3 ml of CHC1₃ /MeOH solution (2:1)for thin layer chromatography. The phases were separated by gentlecentrifugation at 700 rpm for 5 minutes. The organic phase was recoveredfor either thin layer or column chromatography separation.

For thin layer chromatography, labeled arachidonate extracted with CHC1₃/MeOH solution was separated on Silica Gel G TLC plates (Analtech).Twenty ul of a 2 mg/ml internal standard solution of arachidonic acid(Sigma) was combined with 2 to 3 ml of the organic phase. The entiremixture was dried under nitrogen and redissolved in 50 ul of CHC1₃ /MeOHsolution (2:1). A 20 ul sample was counted in 10 ml of Beckman Redi-solvScintillation fluid HP and spotted in Silica Gel G plates. The solventsystem used to develop the plate was a CHC1₃ /MeOH/13.5N NH₃ /H₂ Osolution (70:30:4:1). Thin layer chromatography plates were developed ina glass chamber for 1 to 11/2 hours, air dried, and the spots visualizedin an iodine vapor chamber. Standards of phosphatidyl/choline, lysophosphatidyl choline, and arachidonic acid (Sigma) were made up as 2mg/ml stocks in CHC1₃ /MeOH solution (2:1) and were spotted on the thinlayer chromatography plates. Spots corresponding to arachidonate andphospholipid were scraped and counted in 10 ml Beckman Redi-Solv HPscintillation fluid.

For column chromatography, samples were extracted with hexane/diethersolution and the upper organic phase recovered. An aliquot was appliedto a Silicar CC₄ (Maleinckrodt) column. Columns were prepared using 1 mlof 1:1 slurry of Silicar CC₄ (Maleinckrodt) in hexane/ether solution ina Pasteur pipet (approximately 2 cm height). Columns were rinsed with500 ul of hexane/ether solution before adding the sample (300-600 ul) tothe columns. Columns were eluted with a total of 6 ml of hexane/ethersolution. The 6 ml sample was counted in 10 ml of Beckman Redi-Solv HPscintillation fluid. Thin layer chromatography analysis confirmed thatthe radioactivity eluted was arachidonate.

The inhibition results are illustrated in Table II.

EXAMPLE 68

3-((3-(Acetyloxy)-4-(hexadecyloxy)-butyl)-thio)-N,N,N-trimethyl-1-propanaminium,iodide was prepared by the method of Example 65 as a 1 mg/ml solution inmethanol. Inhibition of phospholipase A₂ activity was measured by a 20,radiochemical assay in which labeled synthetic phosphatidyl cholinesubstrate is converted by porcine pancreatic PLA₂ to free radiolabeledarachidonate and lyso phosphatidyl choline. In the assay, radiolabeledarachidonate is extracted from the reaction mixture and separated fromunreacted substrate by column or thin layer chromatography. Theradioactivity (cpm) in samples is quantified in liquids scintillationcounting.

Labeled substrate (1-stearyl-2-3H-arachidonyl phosphatidylcholine)(Amersham, sp. act. 84 Ci/mmole, 0.025 to 0.2 uCi/assay tube) andunlabeled substrates (Avanti) in sufficient quantity to give 20,000 to50,000 cpm and 10 uM to 1,000 uM final concentration/assay tube) weredried under a stream of nitrogen. The combined substrate was thenredissolved in 0.1M Tris-HCl buffer, pH 9.0, containing 10 mM calciumchloride and 10 mM sodium taurocholate detergent. The mixture wassonicated for 10 to 30 seconds in a Kontes Sonifier to yield ahomogeneous dispersion. The "mixed" micellar substrate was clear. Analiquot was reserved for a cpm count (total substrate). The totalreaction volume was 500 ul; siliconized glassware or plasticware wasused throughout Porcine pancreatic phospholipase A₂ enzyme (Sigma, sp.act. σ690 U/mg protein and preferably 900 U/mg protein) was diluted1:750 or 1:1000 in 0.1M Tris-HCl buffer, ph 9.0 (without Ca⁺⁺ anddetergent).

The test compound was diluted appropriately in phosphate bufferedsaline. 10 ul aliquots of the stock solution were either incubated withenzyme in buffer in the absence of Ca⁺⁺ detergent or were blown under N₂stream with the substrate prior to the addition of buffer. The substrateand buffer were kept on ice until the reaction was started by theaddition of enzyme (preincubated with test compound or diluent, or freshenzyme) to the substrate dispersion in buffer.

Samples (600 ul) were extracted with 3 ml of ChC1₃ /MeOH solution (2:1)for thin layer chromatography. The phases were separated by gentlecentrifugation at 700 rpm for 5 minutes. The organic phase was recoveredfor either thin layer or column chromatography separation.

For thin layer chromatography, labeled arachidonate extracted with CHC1₃/MeOH solurion was separated on Silica Gel G TLC plates (Analtech).Twenty ul of a 2 mg/ml internal standard solution of arachidonic acid(Sigma) was combined with 2 to 3 ml of the organic phase. The entiremixture was dried under nitrogen and redissolved in 50 ul of CHC1₃ /MeOHsolution (2:1). A 20 ul sample was counted in 10 ml of Beckman Redi-solvHP Scintillation fluid and spotted in Silica Gel G plates. The solventsystem used to develop the plate was a CHC1₃ /MeOH/13.5N NH₃ /H₂ Osolution (70:30:4:1). Thin layer chromatography plates were developed ina glass chamber for 1 to 11/2 hours, air dried, and the spots visualizedin an iodine vapor chamber. Standards of phosphatidyl choline, lysophosphatidyl choline, and arachidonic acid (Sigma) were made up as 2mg/ml stocks in CHC1₃ /MeOH solution (2:1) and were spotted on the thinlayer chromatography plates. Spots corresponding to arachidonate andphospholipid were scraped and counted in 10 ml Beckman Redi-Solv HPscintillation fluid.

For column chromatography, samples were extracted with hexane/diethersolution and the upper organic phase recovered. An aliquot was appliedto a Silicar CC₄ (Maleinckrodt) column. Columns were prepared using 1 mlof 1:1 slurry of Silicar CC₄ (Maleinckrodt) in hexane/ether solution ina Pasteur pipet (approximately 2 cm height). Columns were rinsed with500 ul of hexane/ether solution before adding the sample (300-600 ul) tothe columns. Columns were eluted with a total of 6 ml of hexane/ethersolution. The 6 ml sample was counted in 10 ml of Beckman Redi-Solv HPscintillation fluid. Thin layer chromatography analysis confirmed thatthe radioactivity eluted was arachidonate.

The inhibition results are illustrated in Table II.

Example 69

3-((3-(Acetyloxy)-4-(hexadecyloxy)-butyl)-thio)-N,N,N-trimethyl-1-propanaminium,chloride was prepared by the method of Example 66 as a 1 mg/ml solutionin methanol. Inhibition of phospholipase A₂ activity was measured by aradiochemical assay in which labeled synthetic phosphatidyl

is converted by porcine pancreatic PLA₂ to free radiolabeledarachidonate and lyso phosphatidyl choline. In the assay, radiolabeledarachidonate is extracted from the reaction mixture and separated fromunreacted substrate by column or thin layer chromatography. Theradioactivity (cpm) in samples is quantified in liquids scintillationcounting.

Labeled substrate (1-stearyl-2-3H-arachidonyl Ci/mmole, 0.025 to 0.2uCi/assay tube) and unlabeled substrates (Avanti) in sufficient quantityto give 20,000 to 50,000 cpm and 10 uM to 1,000 uM finalconcentration/assay tube) were dried under a stream of nitrogen. Thecombined substrate was then redissolved in 0.1M Tris-HCl buffer, pH 9.0,containing 10 mM calcium chloride and 10 mM sodium taurocholatedetergent. The mixture was sonicated for 10 to 30 seconds in a KontesSonifier to yield a homogeneous dispersion. The "mixed" micellarsubstrate was clear. An aliquot was reserved for a cpm count (totalsubstrate). The total reaction volume was 500 ul; siliconized glasswareor plastic ware was used throughout. Porcine pancreatic phospholipase A₂enzyme (Sigma, sp. act. σ690 U/mg protein and preferably 900 U/mgprotein) was diluted 1:750 or 1:1000

in 0.1M Tris-HCl buffer, pH 9.0 (without Ca⁺⁺ and detergent).

The test compound was diluted appropriately in phosphate bufferedsaline. 10 ul aliquots of the stock solution were either incubated withenzyme in buffer in the absence of Ca⁺⁺ detergent or were blown under N₂stream with the substrate prior to the addition of buffer. The substrateand buffer were kept on ice until the reaction was started by theaddition of enzyme (preincubated with test compound or diluent, or freshenzyme) to the substrate dispersion in buffer.

Samples (600 ul) were extracted with 3 ml of CHC1₃ /MeOH solution (2:1)for thin layer chromatography. The phases were separated by gentlecentrifugation at 700 rpm for 5 minutes. The organic phase was recoveredfor either thin layer or column chromatography separation.

For thin layer chromatography, labeled arachidonate extracted with CHC1₃/MeOH solution was separated on Silica Gel G TLC plates (Analtech).Twenty ul of a 2 mg/ml internal standard solution of arachidonic acid(Sigma) was combined with 2 to 3 ml of the organic phase. The entiremixture was dried under nitrogen and redissolved in 50 ul of CHC1₃ /MeOHsolution (2:1). A 20 ul sample was counted in 10 ml of Beckman Redi-solvHP Scintillation fluid and spotted in Silica Gel G plates. The solventsystem used to develop the plate was a CHC1₃ /MeOH/13.5N NH₃ /H₂ Osolution (70:30:4:1). Thin layer chromatography plates were developed ina glass chamber for 1 to 11/2 hours, air dried, and the spots visualizedin an iodine vapor chamber. Standards of phosphatidyl choline, lysophosphatidyl choline, and arachidonic acid (Sigma) were made up as 2mg/ml stocks in CHC1₃ /MeOH solution (2:1) and were spotted on the thinlayer chromatography plates. Spots corresponding to arachidonate andphospholipid were scraped and counted in 10 ml Beckman Redi-Solv HPscintillation fluid.

For column chromatography, samples were extracted with hexane/diethersolution and the upper organic phase recovered. An aliquot was appliedto a Silicar CC₄ (Maleinckrodt) column. Columns were prepared using 1 mlof 1:1 slurry of Silicar CC4 (Maleinckrodt) in hexane/ether solution ina Pasteur pipet (approximately 2 cm height). Columns were rinsed with500 ul of hexane/ether solution before adding the sample (300-600 ul) tothe columns. Columns were eluted with a total of 6 ml of hexane/ethersolution. The 6 ml sample was counted in 10 ml of Beckman Redi-Solv HPscintillation fluid. Thin layer chromatography analysis confirmed thatthe radioactivity eluted was arachidonate.

The inhibition results are illustrated in Table II.

                  TABLE II                                                        ______________________________________                                        Inhibition of Procine Pacreatic PLA.sub.2                                               67       68         69                                              ______________________________________                                        Percent Inhibition at 10 ug/ml                                                (no. of samples)                                                              @ 2 nM substrate                                                                          54(1)      96.6 ± 4.6                                                                            77(1)                                       concentration           (8)                                                   10 uM       33.0 ± 12.7                                                                           63.2 ± 13.5                                                                           55.3 ± 16.5                                          (2)        (37)       (4)                                         100 uM      --         45.0 ± 13.6                                                                           23(1)                                                              (14)                                                   500 uM      --         15.4 ± 5.7                                                                            --                                                                  (7)                                                   1000 uM     --         8.2 ± 4.6                                                                             --                                                                  (5)                                                   Ic.sub.50 ug/ml                                                               (no. of samples)                                                              @ 2 nM substrate                                                                          8.8(1)     1.55 ± 0.49                                                                           2.8(1)                                      concentration           (2)                                                   10 uM       21.66 ± 6.63                                                                          6.20 ± 3.77                                                                           11.52 ± 10.58                                        (3)        (38)       (3)                                         100 uM      45.8 ± 11.4                                                                           12.34 ± 5.53                                                                          45.56 ± 23.60                                        (3)        (20)       (3)                                         500 uM      107.0(1)   59.58 ± 17.78                                                                         --                                                                  (7)                                                   1000 uM     --         84.56 ± 40.34                                                                         --                                                                  (3)                                                   ______________________________________                                    

I claim:
 1. A compound of the formula ##STR21## wherein R" is a C₂ -C₂₀alkyl group, R₁ ^(") is a C₁ -C₄ alkyl group, y is an integer from 2 to10, and J⁻ is a pharmaceutically acceptable anion.
 2. A method oftreating inflammation which comprises administering an amount of acompound defined in claim 1 which is effective to treat inflammation. 3.The compound4-((3-(dimethylamino)propyl)thio)-1-(hexadecyloxy)-2-butanol, acetate.4. A method of treating inflammation which comprises administering anamount of a compound defined in claim 3 which is effective to treatinflammation.
 5. The compound3-((3-(acetyloxy)-4(hexadecyloxy)butyl)-thio-N,N,N-trimethyl-1-propaminium,iodide.
 6. The compound3-((33-(acetyloxy)-4(hexadecyloxy)butyly)-thio)-N,N,N-trimethyl-1-propaminium,chloride.
 7. A pharmaceutical composition which comprises an amount of acompound as defined in claim 1 which is effective to treat inflammationand a pharmaceutically acceptable carrier.
 8. A pharmaceuticalcomposition which comprises an amount of a compound defined in claim 3which is effective to treat inflammation and a pharmaceuticallyacceptable carrier.
 9. A pharmaceutical composition which comprises anamount of a compound defined in claim 5 which is effective to treatinflammation and a pharmaceutically acceptable carrier.
 10. Apharmaceutical composition which comprises an amount of a compounddefined in claim 6 which is effective to treat inflammation and apharmaceutically acceptable carrier.